Abstract
Early ducts of breast tumors are unequivocally acidic. High rates of glycolysis combined with poor perfusion lead to a congestion of acidic metabolites in the tumor microenvironment, and pre-malignant cells must adapt to this acidosis to thrive. Adaptation to acidosis selects cancer cells that can thrive in harsh conditions and are capable of outgrowing the normal or non-adapted neighbors. This selection is usually accompanied by phenotypic change. Epithelial mesenchymal transition (EMT) is one of the most important switches correlated to malignant tumor cell phenotype and has been shown to be induced by tumor acidosis. New evidence shows that the EMT switch is not a binary system and occurs on a spectrum of transition states. During confirmation of the EMT phenotype, our results demonstrated a partial EMT phenotype in our acid-adapted cell population. Using RNA sequencing and network analysis we found 10 dysregulated network motifs in acid-adapted breast cancer cells playing a role in EMT. Our further integrative analysis of RNA sequencing and SILAC proteomics resulted in recognition of S100B and S100A6 proteins at both the RNA and protein level. Higher expression of S100B and S100A6 was validated in vitro by Immunocytochemistry. We further validated our finding both in vitro and in patients' samples by IHC analysis of Tissue Microarray (TMA). Correlation analysis of S100A6 and LAMP2b as marker of acidosis in each patient from Moffitt TMA approved the acid related role of S100A6 in breast cancer patients. Also, DCIS patients with higher expression of S100A6 showed lower survival compared to lower expression. We propose essential roles of acid adaptation in cancer cells EMT process through S100 proteins such as S100A6 that can be used as therapeutic strategy targeting both acid-adapted and malignant phenotypes.
Highlights
The principle driver of evolutionary processes is the concept of survival of the fittest
In order to study the effects of acidosis on Epithelial mesenchymal transition (EMT) of breast cancer cells at early stages such as ductal carcinoma in situ (DCIS) we first probed the effect of chronic acid adaptation on EMT status of MCF7 breast cancer cell line using quantitative reverse transcription-polymerase chain reaction (Figure 1A) and Immunofluorescent (IF) (Figure 1B) techniques
We concluded acid adaptation is a path to complete EMT and the status we observed can be explained as partial EMT induced by acid adaptation that can be completed by further adaptation to acid or other microenvironmental conditions (Figures 1A,B)
Summary
The principle driver of evolutionary processes is the concept of survival of the fittest. In order for a cancerous cell population to persist, it must be able to adapt and evolve to maintain its’ fitness within a given tumoral environment [1,2,3]. PEMT states compared to complete EMT carry different migratory patterns during cancer metastasis [9, 10], and demonstrate the elevated plasticity of their epithelial progenitors [8] Another cause of EMT can be functional heterogeneity of cancer cells that is the result of genetic and epigenetic makeup as well as their interactions with the microenvironment. It has recently reported that tumor microenvironment conditions such as hypoxia and acidosis can induce EMT [16, 17]
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